COMMENTARY

'Impressive Results' From Stage III Melanoma Studies: ASCO 2020

Jeffrey S. Weber, MD, PhD

Disclosures

August 25, 2020

This transcript has been edited for clarity.

Hello. This is Dr Jeffrey Weber. I'm the deputy director at the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City.

Today I'll be talking to you about a series of adjuvant and/or neoadjuvant studies that were presented at the American Society of Clinical Oncology (ASCO) 2020 virtual meeting.

COMBI-AD

COMBI-AD is an adjuvant trial in resected stage IIIA, IIIB, and IIIC melanoma (per the American Joint Committee on Cancer [AJCC] 7th edition criteria) in patients who had completion lymphadenectomies. The study was a large randomized, blinded phase 3 study of 870 patients where there was an excellent balance between dabrafenib/trametinib for 1 year vs placebo.

This study has now matured. Now at 5 years of follow-up (minimum of 59 months), the primary endpoint of relapse-free survival (RFS) shows a significant difference, with 53% RFS [in the treatment arm] vs 36% for the placebo arm. If you break it down by stage (using the AJCC 7th criteria), the 5-year RFS was 65% for IIIA, 55% for IIIB, and 45% for IIIC. As you would expect, there is a decrement downward with each substage.

In looking at the distant metastasis-free survival, a surrogate for overall survival, there was a significant difference of 65% [in the treatment arm] vs 54% [in the placebo arm], for an absolute difference of 11%.

We heard the initial survival data presented several years ago; however, this was not updated at 5 years and will presumably be updated subsequently.

There were impressive overall results if you look at the patients who went on to other therapy. The majority of patients who were in the targeted therapy arm of dabrafenib/trametinib in COMBI-AD went on to receive immunotherapy. A significantly increased number of patients went on to receive further therapy in the placebo arm compared with the dabrafenib/trametinib arm — something like 27% vs 19%.

KEYNOTE-054

We also heard an update on the KEYNOTE-054 study. This was a study of pembrolizumab versus placebo in virtually the same population of stage IIIA, IIIB, and IIIC resected patients (by the AJCC 7th criteria). All patients had a completion lymphadenectomy. I should point out that this currently is not really the standard of care. But for all of the studies that led to approvals of adjuvant therapies in the past 3 or 4 years, completion lymphadenectomies in stage III patients were carried out.

Now, in the KEYNOTE-054 study, we have moderately mature 3-year RFS data. The data continue to look impressive after the initial presentation with 18 months of follow-up. There is 63% vs 44% RFS for 1 year of pembrolizumab vs the placebo arm. By substage, the 3-year RFS was 81% for IIIA, 65% for IIIB, and 54% for IIIC. Interestingly, if you go back to the COMBI-AD study, IIIB and IIIC are a little bit better. It is also a bit better for the IIIA's, but it is pretty close.

If you look at the breakdown by BRAF V600 E/K, there were really no differences (62% 3-year RFS). Although if you look at the PD-L1 status, PD-L1 positive patients did better, with 65% 3-year RFS vs 57% [for PD-L1 negative patients].

If you look at the breakdown by how patients relapsed, it's a 13% locoregional and nodal relapse rate for the pembrolizumab arm vs 18% for the placebo arm.

For distant metastasis, it's 21% for the treatment vs 32% for the placebo arm — impressive differences for pembrolizumab vs placebo.

Toxicity was updated, and there were no real differences that we would expect. There was an 8% rate of grade 3/4 immune-related adverse events for the pembrolizumab arm vs less than 1% for the blinded placebo arm.

These were very nice updated data, which were quite similar to what we have seen for CheckMate 238 at 3 years. We did not see any CheckMate 238 updates at this year's ASCO. We will probably be seeing that at the European Society for Medical Oncology meeting in September.

PRADO

There was a very interesting abstract at the oral sessions for ASCO about a new concept in neoadjuvant studies, described by Christian Blank, who is the originator of the concept. The PRADO trial is essentially a personalized lymph nodal management trial in the neoadjuvant mode.

Investigators at the Netherlands Cancer Institute, Melanoma Institute of Australia, and elsewhere treated 99 patients. It had an interesting hypothesis where you take the patients with stage IIIB, IIIC palpable and/or measurable disease on a scan and give them neoadjuvant therapy.

But before you start the neoadjuvant therapy, you insert a marker into the "index lymph node," which, in the measurable disease, would be the largest lymph node. You put that marker — a tiny piece of metal that can be injected with a needle — in there at the same time as a biopsy to verify that it is melanoma. All of the patients then get two cycles of what we would call a flipped dose of ipilimumab/nivolumab — that is, ipilimumab is at 1 mg/kg and nivolumab is at 3 mg/kg. They would have further evaluation by scans. The index lymph node would be surgically removed. This is not a completion lymphadenectomy; it's not a total lymph node dissection. If that index lymph node had resolved or disappeared, you would still have the marker. You could have the surgeon go in, find the marker, and remove that particular area or that lymph node if it was still recognizable as the lymph node.

In prior studies (with a few dozen patients), when you looked at this index lymph node in a patient who had a pathologic complete response (pCR), the index lymph node always had a pCR. If you didn't have a pCR, the index lymph node itself did not have a pCR. In these studies, there appeared to be 100% concordance between total lymph node dissection pCR and the index lymph node pCR.

So, based on these data, the idea was, why not just take out the index lymph node? If it shows no evidence of disease, there is no need to go any further. In the prior trials of neoadjuvant ipilimumab/nivolumab done by the same investigators, if you had a pCR, 95% of patients stayed in remission at 2-3 years and had no relapse, implying that if you had a pCR, you probably did not need anything further done.

The other interesting aspect of this trial is that if you had a pCR in the index lymph node that was surgically removed after two cycles of flipped-dose neoadjuvant ipilimumab/nivolumab, you had no further therapy at all. If you had a near pCR, that is, 90% regression, you were treated the same way: no further treatment and no further lymph node dissection. If you had a partial pCR, meaning 50% or more regression but not up to 90%, then you had a completion or total lymph node dissection, but there was no follow-up. If you had no response, meaning less than 50% regression of all disease in the index lymph node, then you had the total or completion lymph node dissection. If you were BRAF mutated, you then got dabrafenib/trametinib; if you were BRAF wild type, you received nivolumab adjuvant therapy for 1 year.

In this study, 91 patients made it past the two cycles; eight or nine patients only got one cycle, and one of them had pretty significant toxicity preventing surgery. There was a significant pCR rate of 50%, 11% rate of near pCR, 10% rate of partial pCR, and 21% had no response. Several percent of patients were inevaluable or did not go on to surgery. If you look at the radiologic response before surgery, there was, again, this classic disparity between radiologic complete response of 45% and pCR or near complete response of 61%. For those 61% of patients who had either a pCR or near pCR of the index node, they avoided subsequent surgery and the morbidity of having a completion lymph node dissection. The quality of life was much more improved in those who avoided the completion lymph node dissection than in those who had it.

We do not have follow-up data yet. This is early days. We do not have any significant RFS data or overall survival data, but we look forward to those data in the next year. It's a very personalized approach in managing neoadjuvant therapy. If it is shown that those with a pCR only in that index lymph node do not relapse, just like the ones in the OpACIN-neo trial, done by the same group, that could change the way we manage our patients with palpable stage IIIB/IIIC disease and or measurable stage IIIB/IIIC disease.

I will give one caveat. Depending on your institution, some see quite a few patients with pathologically positive, palpable nodes. At others, the IIIB/IIIC patients tend to not have palpable adenopathy and tend to not have a measurable disease on a scan or an ultrasound, so the clientele for this sort of approach is limited. But I like it and think it's very creative.

This is Dr Jeffrey Weber. Thank you for your attention.

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